Metastasis is the spread of cancer cells from the place where they first formed to another part of the body. In metastasis, cancer cells break away from the original tumor, travel through the blood or lymph system, and form a new tumor in other organs or tissues of the body.

Previous research has shown that circulating tumor cells (CTCs) are the source of metastases. CTCs are shed from tumors and circulate in the bloodstream. This process can also occur at an early stage of cancer. However, the biological phenomena that trigger the shedding of CTC clusters from a primary cancerous lesion are not fully understood. Now researchers from the University of Basel report that a lack of oxygen is responsible for the separation of CTC clusters from the tumor.

Their findings, “Hypoxia Triggers the Intravasation of Clustered Circulating Tumor Cells,” have been published in the journal Cell Reports and were led by Nicola Aceto, PhD, Swiss National Science Foundation assistant professor and group leader of the Cancer Metastasis Lab at the University of Basel.

“Here, when dynamically labeling breast cancer cells along cancer progression, we observe that the majority of CTC clusters are undergoing hypoxia, while single CTCs are largely normoxic,” noted the researchers.

Using a mouse model for breast cancer, the researchers analyzed the oxygen supply inside the tumors, which are equivalent to human cancer tissue, the detachment of CTCs, and their molecular and cell biological properties. They observed that different areas of the tumor are supplied with different levels of oxygen.

Cancer cells with a lack of oxygen were found wherever the tumor had comparatively fewer blood vessels. The researchers then investigated the CTC clusters that had separated from these tumors and found that they also suffered from a lack of oxygen. The researchers concluded that cells leave the tumor if they do not receive enough oxygen. “It’s as though too many people are crowded together in a small space. A few will go outside to find some fresh air,” explained Aceto.

Further observations revealed that CTC clusters with a lack of oxygen formed metastases faster and shortened the mice’s survival time in comparison to clusters with normal oxygen content.  Aceto noted that if a tumor does not have enough oxygen, the CTC clusters will break away.

“In a tumor, hypoxia is generally expected to be confined to the core and within regions that are poorly vascularized. However, this is an apparent paradox in the context of metastasis biology because metastatic cancer cells need to have access to functional blood vessels to achieve dissemination. We thought of tackling this controversy by directly addressing the role of hypoxia in spontaneous metastasis models in vivo and in relation to CTC generation and metastasis,” explained the researchers.

The researchers stimulated the formation of blood vessels, to boost the supply of oxygen to the tumor cells. As predicted, the number of separating CTC clusters dropped, the mice formed fewer metastases, and they lived longer—however, the primary tumor increased in size significantly.

“This is a provocative result,” added Aceto. “If we give the tumor enough oxygen, the cancer cells have no reason to leave the tumor and metastasize. On the other hand, this accelerates the growth of the primary tumor.”

Moving forward, the researchers are looking forward to applying their findings into a clinical setting where the characteristics of cancer vary from patient to patient. Their findings may lead to new treatment strategies for cancer. “We speculate that therapies aimed at reducing intra-tumor hypoxia, alone or in combination with anticancer agents, may provide a new opportunity to blunt the metastatic spread of cancer in breast cancer patients,” concluded the researchers.

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